PROJECT DESCRIPTION Chronic asthma and obesity, two of today's most troubling threats to child health, are accompanied by inflammation, which impairs skeletal muscle. Muscle, which powers physical activity, plays a much more dynamic role in metabolism and inflammation than earlier realized, and is difficult to study in children with chronic illness. Our overarching hypothesis is that increases in physical activity will ameliorate the long-term effects of early-life inflammatory insults. We will focus on how asthma and obesity influence muscle, using murine models in ways that would not be feasible in children. We will explore the mechanisms by which exercise-training can mitigate the vicious cycle of chronic childhood disease in which physical inactivity exacerbates disease-related inflammation, further impairing muscle and the child's ability to exercise. The shorter lifespan of rats permits us to examine the long-term effects of early-in-life inflammation. To mimic inflammation associated specifically with childhood asthma and obesity, respectively, we have already established murine models of ovalbumin sensitization-and-challenge and neonatal overfeeding. Intriguing strain differences in responses to lung injury and obesity in the rat-some develop systemic inflammation while others do not-will help us isolate the specific mechanisms of early systemic inflammation. Finally, to focus on a mechanism that is emerging as a key common cause of excessive inflammation in both asthma and obesity, we will study episodic hypoxia (EH) using a normobaric hypoxia chamber. Novel, recently published approaches from our laboratory, based on natural behavior of rat pups, will be used to increase physical activity early in life, and its impact on inflammation and muscle will be assessed in adult rats. The relationship among changes in muscle size, phenotype, and function will be used to interpret alterations in inflammatory related cellular and molecular mechanisms. We have targeted specific pathways that link growth and inflammation in muscle, namely the insulin-like growth factor-l (IGF-I), insulin, and interieukin-6 families of growth factors and cytokines, and related mediators (e.g., suppressors of cytokine signaling, NF-KB). We hypothesize that epigenetic mechanisms, which are known to respond to hypoxia and inflammation, play substantial roles in both the immediate impact of disease on muscle and on the cell-memory factors that explain long-term effects of physiological perturbations occurring eariy in life. Consequently, we will study known muscle-related microRNAs (e.g., miR-1 and miR-133), and analyze DNA methylation and histone modifications in the chromatin associated with the likely target genes (MHCs, IGF-I, IGFBPs, IGF receptor) in muscle in neonatal and adolescent animals. To further enhance the integration of the PPG, we will begin to explore the impact of exercise and inflammation on circulating neutrophils and monocytes in their interaction with growing muscle. In conjunction with Projects I and II, these studies will help develop mechanism-based uses of exercise as preventive or adjunctive therapy for a myriad of chronic childhood diseases.